Abstract

Pulmonary arterial hypertension (PAH) and Adams-Oliver syndrome (AOS) are
rare vascular disorders, characterised by severe late-onset and developmental
cardiac abnormalities respectively. Both of them are clinically associated in a
proportion of cases. PAH is a progressive condition that is clinically characterized
by sustained elevation in mean pulmonary artery pressure, through vascular
remodelling with luminal obliteration of small vessels and increased vascular
resistance. In addition, monoclonal proliferation and uncontrolled growth in
pulmonary artery endothelial (PAEC) and smooth muscle (PASMC) cells result in
perturbation and muscularization of the arterial tone. The disease may be
hereditary (HPAH), idiopathic (IPAH) or associated with other conditions, for
example AOS. Most of HPAH and 25% of IPAH cases are associated with
heterozygous mutations of a TGF-β superfamily member transmembrane
receptor type-II, known as BMPR2 on chromosome 2q33. The majority of
mutations suggest haploinsufficiency as the molecular mechanism of disease.
While previous immunohistochemical studies of patient’s lung sections have
reported further loss of BMPR-II than explained by haploinsufficiency, novel
experimentation reported Jun activation domain-binding protein 1 (JAB1) as a
BMPR-II interacting partner. This study has progressed understanding of this
functional interaction in both physiological pathways and in the context of PAH.
AOS disease displays multiple modes of inheritance and it is characterized by
congenital limb defects and scalp cutis aplasia, with notable pulmonary and
cardiovascular involvement in a proportion of cases. Despite advances in
understanding the genetic basis of AOS, for the majority of affected subjects the
underlined causative basis of disease remains poorly characterised. Recent
novel identification of 10 mutations (3 frameshifts, 6 missense and 1 nonsense)
of the NOTCH1 gene in patients clinically characterized with AOS, indicates
NOTCH1 plays a key role in the AOS pathogenesis, and in particular, AOSassociated with congenital heart anomalies. This investigation comprises two
main avenues of research. First, to provide further insight into JAB1 mediated
BMPR-II down-regulation and degradation via the proteasomal pathway and
determination of JAB1 dysregulation and role in the aggressive mitogenic
proliferation potential, through reduction of SMAD signalling and consequently
p38 MAPK and TAK1 activation observed in PAH cells. Second, to assess
dysregulation of the Notch signalling pathway by assessment of NOTCH1 target
genes HEY1 and HES1 expression. Finally, a signalling cross-talk between BMP
and NOTCH1 pathways has been investigated to assess the impact of NOTCH1
AOS-associated mutations on BMP signalling cascade.